Nephrolithiasis (NL) is common, and symptomatic stone episodes cause significant pain, suffering, and economic cost. Much effort has been expended to define metabolic abnormalities that increase urinary supersaturation (SS), and thereby favor stone growth. However, currently available treatments that reduce urinary SS are not completely effective. Therefore, new understanding of additional pathogenic factors is needed to suggest new preventative strategies. Recent studies highlight the importance of NL precursor lesions, including Randall's plaques and plugs within distal tubular lumens. Qur preliminary data suggest that a subset of so-called idiopathic CaOx stones may also begin from tubular plugs. Clinical kidney stone research has lagged because stone passage is the final result of many earlier events, and this series of events likely differs between apparently similar patients. Contributors to urinary SS (e.g. calcium excretion) are clearly important, but other factors such as cellular responses to SS and crystals or protein crystallization inhibitors also contribute to stone formation. We hypothesize that clinical studies to investigate stone pathogenesis have likely been confounded by the (unknown) variety of underlying renal pathologies. Therefore, we plan to carefully phenotype renal stone precursor lesions by direct endoscopic visualization. These carefully pheontyped patients will be used to develop imaging algorithms to noninvasively characterize stone composition and precursor lesions, to define the gene expression of papillary tissue of patients with and without plaque, and determine the urine and stone microbiome of diverse patient types. Specific Aims are: Aim 1 Accurately map kidney stone location and precursor lesions after percutaneous nephrolithotomy in defined groups of patients with idiopathic CaQx stones (n=220), enteric hyperoxaluria (n=15), primary hyperoxaluria (n=5); uric acid stones (n=20); CaP stones (n=30), cystine stones (n=5), and controls without stones (n=30) Aim 2: Define dual energy CT algorithms to predict stone fragility Aim 3: Determine the gene expression profile of papillary tip biopsies with maximal and minimal plaque and plugs. Aim 4: Characterize the microbiome of urine and kidney stones of patients with diverse types of stones. These aims build upon the preliminary data assembled by our multidisciplinary group over the last 4 years.